Per the NCI database, approximately 39,400 new cases of oral squamous cell carcinoma (OSCC) and 7,900 deaths will occur in the U.S. during 2011. Despite extensive efforts, OSCC survival remains among the lowest for solid tumors in the U.S.-a fact which emphasizes the need for better outcomes via more effective OSCC chemoprevention. Previous OSCC chemoprevention trials, which relied upon systemic agent delivery, were largely unsuccessful. The limitations of systemic delivery, which include inability to achieve therapeutic levels at the target site and systemic toxicity, prompted us to develop formulations amenable for local agent delivery. In our pilot oral cancer chemopreventive trial, a topically applied bioadhesive freeze-dried black raspberry (BRB) gel regressed lesions of oral epithelial dysplasia (OED) without any deleterious side effects. For some OED lesions, however, the BRB gel was insufficient. We have subsequently developed a mucoadhesive fenretinide patch that delivers therapeutic levels of the synthetic vitamin A analogue, fenretinide, to oral mucosa. Patch-delivered fenretinide circumvents previously reported systemic toxicities and introduces a chemically distinct, highly promising chemopreventive to the locally delivered OSCC chemoprevention battery. Notably, a cytokine and inflammation-rich environment, which perturbs redox-mediated signaling and thiol dependent proteins, drives the progression of OED to overt OSCC. Furthermore, many cellular pathways modulated by BRB and fenretinide rely upon proteins that contain redox sensitive thiols. We therefore hypothesize that BRB's and fenretinide's abilities to modulate thiol dependent proteins responsible for redox- based signaling and growth regulation are integral to their chemopreventive efficacy. Accordingly, Specific Aims of this proposal are: 1) Investigate the effect of BRB and fenretinide on the regulation of oral keratinocyte growth and transition to the tumorigenic phenotype in vitro., 2) Optimize BRB and fenretinide local delivery formulations for oral cancer chemoprevention., 3) Study the efficacy, metabolism and pharmacokinetics of locally delivered BRB and fenretinide using two complementary murine models. Research methodology includes a variety of biochemical and molecular analyses (Aim 1), pharmaceutical chemistry techniques (Aim 2) and pathology, pharmacokinetics and metabolism studies (Aim 3). Based on their unique mechanisms of action, we anticipate that optimized combined BRB and fenretinide dosing schemes will elicit the best responses-e.g. increased keratinocyte terminal differentiation and diminished proinflammatory and angiogenic cytokine production. In vivo, therapeutic effects will manifest as decreased progression (primary) or tumor size (secondary) due to diminished angiogenesis and keratinocyte and endothelial mobility. Public Health Relevance: Despite costly and extensive research, oral cancer remains a deadly disease. These studies introduce a fresh approach-act before the development of oral cancer by use of locally-delivered cancer- preventing agents to treat precancerous lesions in the mouth without affecting other parts of the body.